DESCRIPTION: Although research over the past few decades has provided significant advances in our understanding of the cell biology of the exocrine pancreas, there has been little progress in our understanding of the pathobiology of pancreatitis, especially ethanol-induced. Furthermore, even though inflammation and cell death are the hallmarks of both human and experimental models of pancreatitis, little work has been done to elucidate the mechanism of the inflammatory response or the relationship between the inflammatory response and specific types of cell death-necrosis and apoptosis. To address this issue, the investigators have designed experiments to elucidate the mechanism of inflammation and cell death in ethanol-induced pancreatitis. They hope that the results will provide insights into strategies that can be used to treat human ethanol-induced pancreatitis. The working hypothesis of the proposed research is that an initial ethanol-induced perturbation of the pancreatic acinar cell leads to the formation of intracellular and extracellular messengers. In turn, the actions of these messengers, either directly or through neutrophils and macrophages, lead to specific types of death (i.e., apoptosis or necrosis) of acinar cells. To test this hypothesis, five specific aims are listed in the application. They are to: 1) develop reproducible models of ethanol-induced pancreatitis; 2) quantitate necrotic cell death, apoptotic cell death, neutrophil infiltration, and macrophage infiltration in the models of ethanol-induced pancreatitis; 3) determine the cytokines that are expressed in the pancreas as well as the cellular source of the production and mechanism of expression; 4) determine the role of each cytokine in the various responses observed such as neutrophil infiltration, macrophage infiltrations, necrosis and apoptosis; 5) determine the cell adhesion molecules that are involved in neutrophil transport to the pancreatic parenchyma; and 6) determine the specific role of neutrophils in the necrosis and apoptosis observed in ethanol-induced pancreatitis.